The studies proposed in this application are designed to test the hypothesis that NKR-P1 proteins are required for the recognition and lysis of specific tumor targets. In addition, the mechanisms by which NKR-P1 proteins generate transmembrane signals for NK cell activation will be determined. The specific aims are: 1) To attempt to reconstitute the lytic defects of NKR-P1 mutant cells (which is defective in the lysis of some, but not all, tumor targets) by transfecting them with the cDNAs encoding the individual NKR-Pl proteins, thus defining the target repertoire for each protein and the requirements for these proteins in NK cell activation. 2) To examine NK cells for the presence of heterodimers composed of different NKR-P1 proteins and to assess the functional significance of heterodimers in NK cell function. 3) To characterize a tyrosine kinase and two tyrosine phosphorylated proteins associated with NKR- P1 in NK cells, and to search for additional lymphocyte activation molecules which might be functionally associated with NKR-P1 in NK cells. 4) To examine the structural motifs of the NKR-Pl molecules required for signal transduction. Specifically, to utilize the polymerase chain reaction to induce site-directed mutations in the NKR-PI cDNA. Following transfection into our NKR-PI- RNK- 16 mutants, the signal transduction profiles of these altered molecules will be determined.